Journal article
Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC
Viruses, v 15(5), 1185
17 May 2023
PMID: 37243271
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (
)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (
)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp
Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp
, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.
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Details
- Title
- Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC
- Creators
- Shilei Ding - Centre Hospitalier de l’Université de MontréalWilliam D Tolbert - Uniformed Services University of the Health SciencesHuile Zhu - California University of PennsylvaniaDaniel Lee - University of PennsylvaniaLorie Marchitto - Centre Hospitalier de l’Université de MontréalTyler Higgins - California University of PennsylvaniaXuchen Zhao - California University of PennsylvaniaDung Nguyen - Uniformed Services University of the Health SciencesRebekah Sherburn - Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USAJonathan Richard - Centre Hospitalier de l’Université de MontréalGabrielle Gendron-Lepage - Centre de Recherche du CHUM, Montreal, QC H2X 0A9, CanadaHalima Medjahed - Centre Hospitalier de l’Université de MontréalMohammadjavad Mohammadi - Drexel University, Chemical and Biological EngineeringCameron Abrams - Drexel University, Chemical and Biological EngineeringMarzena Pazgier - Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USAAmos B Smith, 3rd - University of PennsylvaniaAndrés Finzi - Centre Hospitalier de l’Université de Montréal
- Publication Details
- Viruses, v 15(5), 1185
- Publisher
- MDPI
- Grant note
- R01 AI148379 / NIAID NIH HHS P01 GM056550 / NIGMS NIH HHS UM1 AI164562 / NIAID NIH HHS P01 AI150471 / NIAID NIH HHS P01 AI162242 / NIAID NIH HHS R01 AI129769 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000997248800001
- Scopus ID
- 2-s2.0-85160622266
- Other Identifier
- 991021860619004721
UN Sustainable Development Goals (SDGs)
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Source: SDGs in the Output
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology